Cinacalcet hydrochloride is chemically, (R)-α-methyl-N-[3-[3-trifluoromethyl)phenyl]propyl]-1-napthalenemethanamine hydrochloride. Cinacalcet hydrochloride is represented by the following structure:

Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone (“PTH”) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
Cinacalcet hydrochloride is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with cinacalcet hydrochloride lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood. Cinacalcet hydrochloride is marketed as Sensipar® in USA and as Mimpara® in Europe.
Cinacalcet and its pharmaceutical acceptable salts were disclosed in U.S. Pat. No. 6,211,244 (herein after referred to as the '244 patent). In accordance with the '244 patent, cinacalcet can prepared by reacting 1-acethylnaphthalene with 3-[3-(trifloromethyl)phenyl]propylamine in the presence of titanium isopropoxide to produce an cinacalcet isoimine, followed by treatment with sodium cyanoborohydride in methanol and resolution of the racemic cinacalcet base by chiral liquid chromatography. The synthetic procedure is illustrated in scheme I, below:

According to the '244 patent, cinacalcet can be prepared by reacting 3-fluoromethylcinnamonitrile with diisobutyl aluminum hydride to give aluminum-imine intermediate, which was then reacted with (R)-1-(1-naphthyl)ethylamine, and reducing the cinacalcet imine intermediate thus obtained with sodium cyanoborohydride in ethanol.
Process for the preparation of cinacalcet was reported in Drug of the future, 2002, 27(9), 831-836. According to the journal, cinacalcet can be prepared by reacting (R)-(1-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine, which was then reduced with sodium cyanoborohydride in ethanol. The synthetic procedure was illustrated in scheme II, below:

Process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde was reported in Tetrahedron letters, (45), 8355-8358, (2004) footnote 12. According to the journal, 3-[3-(trifluoromethyl)phenyl]propionaldehyde can be prepared by reduction of 3-(trifluoromethyl)cinnamic acid to the corresponding alcohol followed by swern oxidation to give the desired aldehyde. The synthetic procedure was illustrated in scheme III, below:

PCT publication WO 2008/035212 disclosed a process for preparing 3-[3-(trifluoromethyl)phenyl]propionaldehyde. According to the publication, 3-[3-(trifluoromethyl)phenyl]propionaldehyde can be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propan-1-ol with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and sodium hypochlorite in the presence of potassium bromide in methylene chloride.
PCT publication WO 2008/068625 disclosed a process for the preparation of cinacalcet by reductive amination of 3-(3-trifluoromethylphenyl)propanal with (R)-1-naphthylethylamine in the presence of a sodium triacetoxyborohydride.
PCT publication WO 2007/127445 disclosed a process for the preparation of cinacalcet by reacting 3-(3-trifluoromethylphenyl)propanoic acid with R)-1-naphthylethylamine to give N-[(1R)-1-(1-napthyl)ethyl]-3-(3-trifluoromethyl)phenyl]propanamide, which was then reduced to give cinacalcet and its pharmaceutically acceptable salts. Similar process was also described in PCT publications WO 2008/035381, WO 2008/058235, WO 2008/117299; Tetrahedron Letters 2008 49(1), 13-15 and Synthetic communications 2008 38(10), 1512-1517.
PCT publication WO 2009/153814 disclosed a process for the preparation of cinacalcet. According to the publication, cinacalcet can be prepared by reacting (R)-1-naphthylethylamine with 3-(3-trifluoromethylphenyl)propenaldehyde to give the non isolated (R)-N-[3-[3-(trifluoromrthyl)phenyl]-2-propenylimino-N-[1-(1-napththyl)ethylamine, which was then reduced with sodium borohydride in methanol and hydrogenating the cinacalcet imine intermediate thus obtained.
3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride.
The major problem with the direct preparation of the 3-[3-(trifluoromethyl)phenyl]propionaldehyde from an ester of 3-[3-(trifluoromethyl)phenyl]propionic acid is that the question of reproducibility of the aldehyde formation when used the reagents such as oxalyl chloride. Another problem with this conversation is that the over reduction of the aldehyde formed to the corresponding undesired alcohol. The present invention makes now available a more efficient process for the manufacture of cinacalcet hydrochloride in particular by providing efficient manufacture of 3-[3-(trifluoromethyl)phenyl]propionaldehyde. According to the present invention, 3-[3-(trifluoromethyl)phenyl]propionaldehyde can prepared from ester of 3-[3-(trifluoromethyl)phenyl]propionic acid in a single step. It has been found that the ester of 3-[3-(trifluoromethyl)phenyl]propionic acid can be reduced selectively to the corresponding aldehyde by choosing suitable reaction condition, avoiding the formation of excess of the undesired corresponding alcohol.
2-[3-(Trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal and (R)-1-(naphthyl)ethylamine are potential impurities in cinacalcet hydrochloride.
The chemical formula of (R)-1-(naphthyl)ethylamine may be represented as:

The chemical formula of 2-[3-(trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal may be represented as:

The present invention is intended to enhance the purity of cinacalcet hydrochloride. In particular, the present invention is directed to reduce or remove 2-[3-(trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal and (R)-1-(naphthyl)ethylamine impurities from cinacalcet hydrochloride.
Thus, one object of the present invention is to provide a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
Another object of the present invention is to provide an improved process for the preparation of cinacalcet hydrochloride.
Yet another object of the present invention is to provide a process for the purification of cinacalcet hydrochloride.